Hippo/Mst1 overexpression induces mitochondrial death in head and neck squamous cell carcinoma via activating β-catenin/Drp1 pathway

Abstract

Mammalian Ste20-like kinase 1 (Mst1) is associated with cell apoptosis. In the current study, we explored the regulatory effects of Mst1 on squamous cell carcinoma of the head and neck (SCCHN) in vitro. SCCHN Cal27 cells and Tu686 cells were transfected with adenovirus-loaded Mst1 to detect the role of Mst1 in cell viability. Then, siRNA against Drp1 was transfected into cells to evaluate the influence of mitochondrial fission in cancer survival. Our data illustrated that Mst1 overexpression promoted SCCHN Cal27 cell and Tu686 cell death via activating mitochondria-related apoptosis. Cells transfected with adenovirus-loaded Mst1 have increased expression of DRP1 and higher DRP1 promoted mitochondrial fission. Active mitochondrial fission mediated mitochondrial damage, as evidenced by increased mitochondrial oxidative stress, decreased mitochondrial energy production, and reduced mitochondrial respiratory complex function. Moreover, Mst1 overexpression triggered mitochondria-dependent cell apoptosis via DRP1-related mitochondrial fission. Further, we found that Mst1 overexpression controlled mitochondrial fission via the β-catenin/DRP1 pathways; inhibition of β-catenin and/or knockdown of DRP1 abolished the pro-apoptotic effects of Mst1 overexpression on SCCHN Cal27 cells and Tu686 cells, leading to the survival of cancer cells in vitro. In sum, our results illustrate that Mst1/β-catenin/DRP1 axis affects SCCHN Cal27 cell and Tu686 cell viability via controlling mitochondrial dynamics balance. This finding identifies Mst1 activation might be an effective therapeutic target for the treatment of SCCHN.

Suppressing DRP1-mediated mitochondrial fission and mitophagy increases mitochondrial apoptosis of hepatocellular carcinoma cells in the setting of hypoxia

“…Besides inhibiting DRP1 phosphorylation, Mdivi-1 down-regulated DRP1 expression in this study. As reported by other authors 32,38 , inhibition of DRP1 by Mdivi-1 decreased the DRP1 expression in their experiments. Mdivi-1 is reported to have additional targets, which may be responsible for DRP1 down-regulation.…”

“…DRP1 is essential in mitochondrial fission and mitophagy initiation. Some studies have illustrated the existence of cytosolic Ca 2+ /DRP1 or Wnt/β-catenin/DRP1 axis in mitochondrial function regulation for cancer [31][32][33] . Multiple posttranslational modifications of phosphorylation, ubiquitination and sumoylation regulate the functions of DRP1 34 .…”

Mst2 Overexpression Inhibits Thyroid Carcinoma Growth and Metastasis by Disrupting Mitochondrial Fitness and Endoplasmic Reticulum Homeostasis

“…Similarly, overexpressed Mst1 caused mitochondria-dependent breast cancer cell apoptosis via the JNK–Drp1 pathway [ 60 ]. Another study reported the tumor-suppressive effects of Mst1 on cancer cell proliferation and metastasis by activating the β -catenin/Drp1 axis [ 61 ]. Furthermore, Mst1 overexpression impaired the proliferation and migration of colorectal cancer cells by activating the JNK/ p 53/Bnip3 pathway [ 62 ].…”

Crosstalk of the Wnt/β-Catenin Signaling Pathway in the Induction of Apoptosis on Cancer Cells

“…Mst1 overexpression causes apoptosis by increasing ROS generation, the levels of the Bax proapoptotic protein, and the activity of caspase-9, while decreasing the antioxidant activity of SOD, GSH, and GPX, as well as the levels of the antiapoptotic protein Bcl-2 in the squamous cell carcinoma of the head and neck (SCCHN) Cal27 cell line and in Tu686 cells; the mechanism is thought to involve the regulation of mitochondrial fission via the β-catenin/DRP1 pathways [ 254 ]. An inhibition of the Wnt/β-catenin pathway by DKK1 was already reported to lower Mst1-mediated DRP1 upregulation, and therefore apoptosis, in Cal27 and Tu686 cells [ 254 ].…”